New Potential Therapeutics

Findings from several epidemiological studies have revealed that major depressive disorder (MDD) is associated with increased cardiovascular risk and a higher rate of complications and new ischemic events in subjects with already established cardiovascular diseases (CVD). Although the exact pathophysiological mechanisms remain unclear, autonomic dysfunction consisting of increased sympathetic activity and reduced cardiac vagal tone has been proposed as an important contributing factor to this relationship. Recent studies have evidenced that the brain circuitry for mood regulation overlaps with the circuits for autonomic nervous system (ANS) modulation. Therefore, functional alterations in areas such as the ventromedial prefrontal cortex, orbitofrontal cortex, cingulate cortex, hypothalamus, amygdala and insula could be implicated in both the pathogenesis of major depression and cardiovascular autonomic dysregulation. This shared neural circuitry is an optimal target for new therapeutic developments aimed to reduce the impact of this comorbidity.

Vagus nerve stimulation (VNS) is an FDA approved treatment for MDD, however some disadvantages of VNS (e.g. surgical risks, lesions of the vagus nerve, infection, hoarseness, shortness of breath) limit broad applicability. In the last decade, an alternative low-risk, non-invasive (transcutaneous) and inexpensive method involving the electrical stimulation of the auricular branch of the vagus nerve was proposed. Previous studies have suggested modulatory effects of tVNS on the cardiac autonomic nervous system; however, although brain circuitry for mood/ anxiety and ANS regulation are overlapping, VNS modulation of ANS has not been examined in association with mood response. In the present study we will identify whether acute tVNS effects on brain circuitry in MDD are associated with modulation of mood, anxiety and vagal tone and whether tVNS can modulate the brain's response to stress (a trigger for MDD).  The work will advance our understanding of the shared pathophysiology of mood and cardiac regulation and how this may contribute to symptom alleviation using a less invasive form of VNS that may have wider applications.

Thus, this project has the ultimate potential to 1) discover a novel treatment for comorbid MDD and CVD; 2) decrease the risk of CVD in MDD patients; and 3) elucidate the neurobiologic circuitry and physiology associated with tVNS therapeutic response.